Professional Documents
Culture Documents
Empagliflozin (Jardiance) : National Drug Monograph
Empagliflozin (Jardiance) : National Drug Monograph
Empagliflozin (Jardiance)
VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives
The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions.
Updates will be made when new clinical data warrant additional formulary discussion. Documents will be placed in the
Archive section when the information is deemed to be no longer current.
Executive Summary
Efficacy Reduction in A1C generally <1%
11-29% of patients treated with empagliflozin had ≥5% weight loss from
baseline (magnitude of change was less when combined with drugs known to
cause weight gain such as SU, TZDs, insulin)
Safety Similar to the other agents in the SGLT2 inhibitor class, there is an increased
risk in genital mycotic infections, urinary tract infections, hypotension, and
small increases in serum creatinine and decreases in eGFR
Low risk for hypoglycemia
Can reduce systolic blood pressure (means ranged from 2.9 to 5.2mmHg) and
diastolic blood pressure (means ranged from 1.0 to 2.5mmHg)
Other Considerations First glucose-lowering agent to show a reduction in cardiovascular (CV) events.
The study was conducted in patients with history of CV disease. It is unknown
at this time if this is a class effect of the SGLT2 inhibitors or if the findings
apply to those without preexisting CV disease.
Do not initiate in patients with eGFR < 45mL/min/1.73m2
High cost (SGLT2 inhibitors are approximately $200+/month)
Background
Purpose for Review The purpose of this monograph is to evaluate the available evidence of safety,
tolerability, efficacy, cost, and other pharmaceutical issues that would be
relevant to evaluating empagliflozin (EMP) for possible addition to the VA
National Formulary
October 2015 1
Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
Empagliflozin Monograph
Review of Efficacy
This review is limited to Phase 3 trials and the approved doses empagliflozin 10mg and 25mg. The trials range in
duration from 12-104 weeks (Appendix 1). Several of the 12-24week trials have 78-week extension data available
(Table 1). The majority of primary trials compare empagliflozin to placebo and 2 have an active comparator
(sitagliptin and glimepiride). Two trials evaluate monotherapy and the others are add-on to other diabetes drugs.
There are 3 trials conducted in special populations (chronic kidney disease, hypertension, and obese patients) and a
long-term cardiovascular safety trial
Glycemic Efficacy
Average baseline A1C ranged between 7.9%-8.3%. The mean A1C for most studies was approximately 8.0%;
patients enrolled in the add-on to insulin trial had higher baseline averages (A1C 8.3%). Rescue therapy with
another anti-glycemic agent was allowed for most trials as defined by protocol.
In Kovacs et al, 75.5% of patients were on pioglitazone + metformin; the remainder was taking pioglitazone alone.
For the comparator study by Ridderstrale et al., the mean daily dose of glimepiride was 2.7mg (maximum approved
dose 8mg). The baseline mean daily dose of insulin in study 33 was approximately 47units. In the trial of obese
patients by Rosenstock et al., 71% were taking metformin in addition to multi-dose insulin. The mean baseline basal
and prandial insulin doses were approximately 50 and 40 units respectively. Insulin doses for both insulin trials
were to remain stable during the first 18 weeks of the study and could be adjusted according to treat-to-target for the
remainder of the study. In the chronic kidney disease (CKD) study where study drug was added to baseline
treatment, over 50% of patients were using insulin and or SUs.
The mean change in A1C ranged from -0.6 to -0.8% except for the multi-dose insulin trial where the mean change
was approximately -1.2%. There was very little difference between the 10mg and 25mg doses (approximately 0.1%
difference). An A1C <7% was achieved by 24-38% of patients receiving empagliflozin 10mg and 30-44% receiving
25mg. Changes in fasting plasma glucose (FPG) followed a similar pattern. Improvement in A1C was similar for
sitagliptin and empagliflozin (monotherapy study) and glimepiride and empagliflozin (add-on to metformin);
however, there was less improvement in FPG with sitagliptin or glimepiride relative to empagliflozin. Appendix 1
Fewer patients receiving empagliflozin required rescue therapy compared to placebo. Need for rescue was similar
for empagliflozin and sitagliptin and significantly less with empagliflozin compared to glimepiride.
October 2015 2
Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
Empagliflozin Monograph
In the insulin trials, the mean change in insulin dose between weeks 18-78 in the basal insulin ± metformin/SU trial
was -1.21, -0.47, and 5.45 units for EMP10, EMP25, and placebo respectively. For the multidose dose insulin trial,
the mean change in total daily dose (basal+prandial) was 1.3, -1.1, and 10.2 units for EMP10, EMP25, and placebo
respectively.
The dedicated renal impairment study evaluated improvement in A1C according to baseline renal function. The
change in A1C for empagliflozin 25mg and placebo respectively was -0.63% and 0.06% (eGFR 60 to < 90); -0.37%
and 0.05% (eGFR ≥30 to < 60); 0.04 and -0.18 (eGFR ≥15 to <30) . Urinary glucose excretion is proportional
to
GFR; therefore, it is not unexpected that a lesser response was seen in those with greater renal impairment.
Empagliflozin is not approved for use in those with eGFR <45mL/min per 1.73m2.
Post-prandial glucose (PPG) was evaluated in a subset of patients in 3 trials. Empagliflozin decreased mean 2-hour
PPG by approximately 50mg/dL (add-on to metformin) and 36mg/dL (add-on to metformin+SU). In the head-to
head trial, 2-hour PPG was reduced by 46.4mg/dL (EMP25) and 32.4mg/dL (glimepiride).
Three of the 24-week placebo-controlled trials included an open-label empagliflozin arm in a subgroup patients with
a baseline A1C >10%. The mean change in A1C was -3.7% (monotherapy), -3.23% (add-on to metformin), and
The extension trials from 4 of the placebo-controlled trials show the A1C lowering effect is maintained (Table 1).
In addition, extension data were available for two 12-week Phase 2b dose-finding trials with active comparator
arms. In the monotherapy study, the reduction in A1C was numerically greater with metformin. The add-on to
metformin study showed numerically greater reduction in A1C with EMP25 compared to EMP10 and sitagliptin.
October 2015 3
Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
Empagliflozin Monograph
Weight
The urinary loss of glucose using SGLT2 inhibitors has been estimated to be 60-80g daily, which equates to
approximately 200-300 kcal/day. There was significantly greater weight loss with empagliflozin compared to
placebo. The magnitude of loss decreased when combined with drugs known to cause weight gain (SUs, TZDs,
insulin). More patients randomized to empagliflozin had ≥5% decrease in weight (Appendix 1).
In the empagliflozin vs. glimepiride trial, change in weight was -3.1kg and 1.3kg for respectively; 27.5% of EMP25
patients achieved ≥5% weight loss compared to 3.8% in the glimepiride group. In the monotherapy trial, there was
significantly greater weight loss with empagliflozin (-2.4kg) than sitagliptin (0.2kg).
The 76-78 week extension trials from 4 of the placebo-controlled trials show the reduction in weight persists (Table
1). The extension data for two 12-week Phase 2b dose-finding trials show greater weight reduction with
empagliflozin compared to metformin or sitagliptin.
Blood Pressure
Decrease in mean systolic blood pressure (SBP) ranged from 2.9 to 5.2mmHg. Decrease in mean diastolic blood
pressure (DBP) ranged from 1.0 to 2.5mmHg (Appendix 1).
A dedicated 12-week hypertension study was conducted in patients receiving up to 2 antihypertensive medications.
Patients with mean seated BP ≥160 /100mmHg were excluded. The percentage of patients taking 1 or 2
antihypertensive medications at baseline was 43% and 47% respectively. The dose of baseline antihypertensive
medications was to remain unchanged if possible. Mean baseline SBP was 142mmHg (office measurement) and
131mmHg (ambulatory 24h monitoring). Mean baseline DBP was 84mmHg and 75mmHg respectively for office
and ambulatory measurements.
The change in 24-h SBP and DBP was greater with empagliflozin compared to placebo. The change in daytime
measurements was greater than the nighttime measurements and greater with office measurements than the
ambulatory measurements. Mean 24-h BP was also analyzed according to those with BP≥130/80 and <130/80.
Those with BP≥130/80 had a greater change than those with BP <130/80 (Table 2).
The extension trials from 4 of the placebo-controlled trials show that the reduction in BP persists (Table 1). The
extension data for two 12-week Phase 2b dose-finding trials show greater BP reduction with empagliflozin
compared to metformin or sitagliptin.
Cardiovascular Outcomes
EMPA-REG OUTCOME evaluated CV outcomes and mortality in patients with type 2 diabetes. Patients (n=7034)
with established CV disease (e.g., history of MI, CAD, CABG, history of stroke, peripheral occlusive arterial
disease, unstable angina) were randomized to empagliflozin 10mg, 25mg or placebo in addition to their usual
diabetes drugs. Randomization was stratified according to baseline A1C, BMI, geographic region, and renal
October 2015 4
Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
Empagliflozin Monograph
function. The primary endpoint was the composite of cardiovascular (CV) death, nonfatal myocardial infarction
(MI), and nonfatal stroke.
Approximately 71% of patients were male and 72% white. Baseline diabetes medications were as follows:
approximately 74% metformin, 48%, insulin (median daily dose 53 units), SU 43%, DPP4 inhibitor 11%, TZD
4.3%, and GLP-1 agonist 2.8%. Approximately 30% were on monotherapy and 49% on dual therapy.
Prior CV events were as follows: MI (47%), CAD (76%), CABG (25%), stroke (23%), and POAD (21%). Cardiac
medications included aspirin (85%), statins (77%), fibrates (0%), beta-blockers (64%), RAS blocking agents (80%),
and calcium channel blockers (30%).
Mean baseline values were A1C 8.1%, BMI 30.6, weight 86.4kg, SBP/DBP 135/77mmHg, and eGFR 74(22%, 52%
and 26% had eGFR >90, 60 to <90, and 30 to <60 respectively).
The median treatment duration was 2.6 years and the median observation time was 3.1 years. The percentage of
patients who had a primary composite outcome event was significantly lower with empagliflozin than placebo
(Table 6). This outcome was driven by a reduction in CV mortality as the difference for nonfatal MI and stroke was
not significant. Other secondary outcomes that showed a significant reduction in events were all-cause mortality
and hospitalization for heart failure.
Several factors remain unknown at this time, including the mechanism explaining these findings, whether benefits
extend to those without underlying CV disease, and if this is a class effect of the SGLT2 inhibitors.
Safety
(for more detailed information refer to the product package insert)
Comments
Boxed Warning None
Contraindications History of serious hypersensitivity reaction to empagliflozin
Severe renal impairment, end-stage renal disease, or dialysis
Warnings/ Hypotension: Empagliflozin causes intravascular volume contraction. Symptomatic hypotension
Precautions may occur after initiation of empagliflozin particularly in patients with renal impairment, elderly
October 2015 5
Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
Empagliflozin Monograph
patients, patients with low systolic blood pressure and those taking diuretics. Volume status should
be assessed and corrected before initiating empagliflozin in patients with these characteristics.
Monitor for signs and symptoms after initiating therapy and increase monitoring in clinical
situations where volume contraction is expected.
Impairment in renal function: Empagliflozin increases serum creatinine and decreases eGFR. The
risk of impaired renal function is increased in elderly patients and patients with moderate renal
impairment. Evaluate renal function prior to initiating empagliflozin and periodically thereafter.
Hypoglycemia with concomitant use with insulin or insulin secretagogues: The risk of
hypoglycemia can be increased when empagliflozin is combined with insulin or insulin
secretagogues (e.g., sulfonylureas). A lower dose of insulin or insulin secretagogue may be needed
to minimize the risk.
Genital mycotic infections: Empagliflozin increases the risk of genital mycotic infections. Patients
with a history of genital mycotic infections were more likely to develop genital mycotic infections.
Monitor and treat as appropriate.
Urinary tract infections: empagliflozin increases the risk for UTI. Monitor and treat as
appropriate.
The incidence of hypoglycemia was low and similar to placebo when empagliflozin is used as
monotherapy or in combination with metformin, or pioglitazone. The incidence of hypoglycemia
is higher when combined with other drugs known to cause hypoglycemia such as SUs or insulin
(Appendix 2). In the insulin trials, although the incidence of hypoglycemia was increased, the
combination with empagliflozin was comparable to the placebo + insulin ± orals arms.
In the 104-week trial of empagliflozin vs. glimepiride, the incidence of hypoglycemia was 2% and
24% respectively.
Severe hypoglycemia with empagliflozin was uncommon and reported only in the insulin and CKD
(approximately 35% using insulin) trials.
The incidence of hypoglycemia in the extension trials follows a similar pattern to the parent trial
(Table 3).
October 2015 6
Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
Empagliflozin Monograph
Infection
The SGLT2 inhibitors increase urinary glucose excretion; therefore, there is increased potential for
fungal growth in perineum and bacterial growth in urinary tract. There is an increased rate of UTIs
and genital mycotic infections with empagliflozin compared to placebo/active comparators.
According to pooled results of 5 placebo-controlled trials (Roden, Kovacs, Study 33, and both
Haring trials), the incidence of genital mycotic infection in females was 5.4%, 6.4%, and 1.5% for
EMP10, EMP25, and placebo respectively. In males, the rate was 3.1%, 1.6%, and 0.4 %
respectively. This AE led to discontinuation of study drug in 0.2% of empagliflozin-treated
patients versus none in the placebo group.
In the active comparator arms, genital infections occurred more frequently with empagliflozin than
glimepiride (2%) or sitagliptin (1%). Results according to individual trials are shown in
Appendix 2.
The pooled incidence of UTIs in females was 18.4%, 17.0%, and 16.6% for EMP10, EMP25, and
placebo respectively. In males, the incidence was 3.6%, 4.1%, and 3.2 % respectively. Patients
with chronic or recurrent UTIs were at higher risk of UTI. For both UTI and genital infections, the
majority of patients had a single episode of infection. In the overall population, this AE led to
discontinuation of study drug in 0.1%, 0.2%, and 0.1% of patients receiving EMP10, EMP25, and
placebo respectively. The risk of UTIs is increased in older patients (≥75 years old) to 15.7%,
15.1%, and 10.5% respectively and in those with worsening renal function (results not shown).
The overall (male and female) incidence of UTIs and genital infections for the extension trials are
shown in Table 3.
Volume Depletion
Empagliflozin can cause osmotic diuresis due to increased urinary glucose; therefore, adverse
events related to volume depletion (dehydration, hypovolemia, orthostatic hypotension,
hypotension, syncope) were evaluated. The pooled incidence in the 5 placebo-controlled trials
(Roden, Kovacs, Study 33, and both Haring trials) was 0.5%, 0.3%, and 0.3% respectively in
October 2015 7
Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
Empagliflozin Monograph
Patients with impaired renal function, those taking loop diuretics, and the elderly are at higher risk
for these events. In the pooled results for the 5 placebo-controlled trials, volume depletion-related
AEs in those ≥75 years old was 2.3%, 4.4%, and 2.1% for EMP10, EMP25, and placebo
respectively.
The safety data base for 18 clinical trials show an increased risk of volume-related AEs for those
taking loop diuretics at baseline for empagliflozin versus the comparators (Table 4). The risk is
less evident for empagliflozin versus comparators when all diuretic use is compared.
In the empagliflozin vs. glimepiride trial, there was no difference between groups (1% each) in
events consistent with volume depletion.
Dizziness was reported more often with empagliflozin in the multi-dose insulin study (2.7%, 6.9%,
and 1.1% for EMP10, EMP25, and placebo respectively).
In the hypertension study, 15.5%, 19.7%, and 16.5% of patients randomized to EMP10, EMP25,
and PBO respectively had a positive orthostatic BP test at baseline. At week 12, the orthostatic BP
test was positive in 25.95, 29.3%, and 20.1% of patients respectively. One patient each receiving
EMP10 and PBO had events consistent with volume depletion.
Events consistent with volume depletion were assessed in the long-term CV trial. The reported
incidence was 4.9%, 5.3%, and 4.9% for EMP10, EMP25, and placebo respectively.
Renal Safety
The pooled results for change in serum creatinine (SCr) and eGFR for the four 24-week placebo-
controlled trials are shown in Table 5. There was a small increase in mean SCr and decrease in
mean eGFR in the empagliflozin groups at week 24.
Results from the CKD study for those with moderate renal impairment are also shown. Baseline SCr
and eGFR was approximately 1.5mg/dL and 45ml/min/1.73m2 respectively. This group had greater
change in renal function compared to those in the pooled trials; the changes were similar at weeks 24
and 52.
October 2015 8
Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
Empagliflozin Monograph
In the long-term CV safety trial, acute renal failure was reported in 5.2%, 5.3%, and 6.6% of
patients in the EMP10, EMP25, and placebo groups respectively. The incidence of acute renal
injury was 1.1%, 0.8%, and 1.6% respectively. The change in SCr and eGFR were similar between
empagliflozin and placebo. The full analysis on renal outcomes has not yet been performed.
Urine albumin/creatinine ratio (ACR) was assessed in the CKD trial and the empagliflozin vs.
glimepiride trial. In the CKD trial, fewer patients receiving empagliflozin 25mg compared to
placebo progressed from no albuminuria to microalbuminuria and microalbuminuria to
macroalbuminuria. For example in stage 3 CKD 12.2% and 22.2% of patients receiving EMP25
and placebo respectively had a shift from no albuminuria to microalbuminuria and 2.0% and 11.4%
respectively had a shift from microalbuminuria to macroalbuminuria.
Similarly, more patients receiving empagliflozin shifted from a higher category to a lower category
of albuminuria. In those with stage 3 CKD, 32.6% of those receiving empagliflozin and 8.6%
placebo shifted from macroalbuminuria to microalbuminuria. The shift from micro- to no
albuminuria was 27.5% and 21.4% respectively.
In the empagliflozin vs. glimepiride trial, there was a decrease in the ACR with empagliflozin and
an increase with glimepiride.
Increase in hematocrit
Based on 4 placebo-controlled trials, the hematocrit increased by a median of 2.8% each for
EMP10 and EMP25 and decreased by 1.3% in the placebo groups. At the end of treatment, 2.7%,
3.5%, and 0.6% of those who had normal values at baseline, had values above the upper range of
normal respectively. The increases appear to be reversible upon discontinuation of empagliflozin.
In the long-term CV study, the mean change in hematocrit from baseline was 4.8%, 5.0%, and
0.9% for EMP10, EMP25, and placebo respectively.
Effect on lipids
According to pooled data from the placebo-controlled trials, LDL-C (baseline value ~90mg/dL)
increased by 4.6%, 6.5%, and 2.3% of patients receiving EMP10, EMP25, and placebo
respectively. In the sitagliptin arm of the Roden trial, LDL-C increased by 1%. In the EMP25 vs.
glimepiride study, LDL-C increased by 7.9% and 1.7% respectively.
October 2015 9
Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
Empagliflozin Monograph
Bone Safety
A higher rate of bone fractures, most commonly upper extremity fractures, has been reported with
canagliflozin, another SGLT2 inhibitor.
According to the safety database for empagliflozin, fractures occurred with similar frequency
between empagliflozin (1.3%) and comparators (1.5%). There was no difference frequency among
treatment group for fractures according to small vs large bones or upper vs lower extremities.
The long-term CV trial evaluated bone fractures as a safety outcome. There was no difference
between empagliflozin and placebo. The incidence was 3.9%, 3.7%, and 3.9% for EMP10,
EMP25, and placebo respectively. It is not known if the risk changes with use beyond 3 years.
Malignancy
In the clinical trials of another SGLT2 inhibitor, dapagliflozin, an imbalance of bladder cancers
was observed. The labeling for dapagliflozin states it should not be used with active bladder
cancer and used with caution in those with a prior history.
In the empagliflozin safety database of 18 trials, the incidence of all malignancies was 1.02%,
1.11%, 0.91%, and 0.90% for EMP10, EMP25, placebo, and all comparators. The incidence when
evaluated according to those with an onset 6 or more months after initiation of study drug was
0.61%, 0.54%, 0.45%, and 0.53% respectively.
There was a numeric imbalance not favoring empagliflozin for lung neoplasms and malignant
melanoma. There were 6 cases of lung neoplasms in the empagliflozin group and none in the
comparators; one case was primary colon which metastasized to the lung. Patients were current or
prior smokers. It was noted that the lung malignancies were of differing cell types which is not
typical for drug-associated malignancy.
There were 6 cases of melanoma in the empagliflozin group and none among the comparators.
Two patients had prior melanoma, one had multiple prior skin cancers, and one had sun-damaged
skin.
Diabetic ketoacidosis
The FDA has issued a warning that the SGLT2 inhibitors canagliflozin, dapagliflozin, and
empagliflozin may lead to ketoacidosis. A search of the FDA Adverse Event Reporting System
(FAERS) database identified 20 cases of acidosis reported as diabetic ketoacidosis (DKA),
ketoacidosis, or ketosis in patients treated with SGLT2 inhibitors from March 2013 to June 6,
2014. Since June 2014, they have continued to receive additional FAERS reports for DKA and
ketoacidosis in patients treated with SGLT2 inhibitors.
Atypically, glucose levels were only mildly elevated at less than 200 mg/dL in some reports
(patients with type 1 diabetes who have DKA usually have glucose levels above 250 mg/dL; DKA
does not routinely occur in patients with type 2 diabetes). Half of the cases reported potential
triggers for DKA, including acute illness or recent significant changes such as infection, urosepsis,
trauma, reduced caloric or fluid intake, and reduced insulin dose. All cases resulted in emergency
room visits or hospitalization to treat the acidosis.
The FDA is continuing to investigate this safety issue and will determine whether changes are
needed in the prescribing information.
Patients should pay close attention for any signs of ketoacidosis and seek medical attention
immediately if they experience symptoms such as difficulty breathing, nausea, vomiting,
abdominal pain, confusion, and unusual fatigue or sleepiness. Health care professionals should
October 2015 10
Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
Empagliflozin Monograph
evaluate for the presence of acidosis, including ketoacidosis, in patients experiencing these signs or
symptoms; discontinue SGLT2 inhibitors if acidosis is confirmed; and take appropriate measures
to correct the acidosis and monitor sugar levels.
Adverse Reactions
Common adverse The following most common adverse events (Table 7) are pooled from the four 24-week
reactions and one 18-week placebo controlled trials (Roden, Haring 2013, Haring 2014, Ridderstrale,
study 33). Hypoglycemia, urinary tract and genital infections are not included here and are
discussed separately.
Table 7: !dverse Events Reported in ≥2% of Patients Treated with Empagliflozin and
Greater than Placebo (%)
EMP10 (n=999) EMP25 (n=977) PBO (n=995)
URI 3.1 4.0 3.8
↑ urination 3.4 3.2 1.0
Dyslipidemia 3.9 2.9 3.4
Arthralgia 2.4 2.3 2.2
Nausea 2.3 1.1 1.4
Adverse events in the head-to-head empagliflozin and glimepiride trial were generally
balanced; events reported more often with glimepiride were hypoglycemia (25% vs. 4%),
Sitagliptin was an active comparator arm in the Roden trial. Dyslipidemia was reported in
Death/Serious
See Appendix 2
adverse reactions
Discontinuations
See Appendix 2
due to AEs
Drug Interactions
Drug-drug interactions No clinically relevant pharmacokinetic interactions based on in vitro and in vivo
testing.
Coadministration with diuretics results in increased urine volume and frequency of
voids
Coadministration with insulin or insulin secretagogues increases the risk for
hypoglycemia
Drug-food interactions None
Drug-lab interactions Monitoring glycemic control with urine glucose tests is not recommended in patients
taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will
lead to positive urine glucose tests. Use alternative methods to monitor glycemic control
October 2015 11
Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
Empagliflozin Monograph
Risk Evaluation
As of 9/24/15
Sentinel event None
advisories Sources: ISMP, FDA, TJC
Look-alike/sound-alike NME Drug Name Lexi-Comp First DataBank ISMP Clinical Judgment
error potentials !Empagliflozin 10, None None None Canagliflozin
25 mg tab Dapagliflozin
Empagliflozin and linagliptin
Empagliflozin and metformin
Other Considerations
First glucose lowering agent to reduce CV events.
Will need to wait for results of the CV trials for canagliflozin and dapagliflozin to see if this is a class effect.
October 2015 12
Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
Empagliflozin Monograph
In humans, kidney maturation occurs in utero and in the first 2 years of life.
Because of the potential for serious adverse reactions to the nursing infant, a
decision should be made to discontinue empagliflozin or nursing taking into
account the importance of the drug to the mother.
Renal Impairment Glycemic efficacy is decreased in patients with worsening renal function. Risk
of adverse reactions (i.e., risk of renal impairment, volume depletion, UTIs) is
increased in patients with worsening renal function.
Hepatic Impairment In subjects with mild, moderate, and severe hepatic impairment according to the
Child-Pugh classification, AUC of empagliflozin increased by approximately
23%, 47%, and 75%, and Cmax increased by approximately 4%, 23%, and 48%,
respectively, compared to subjects with normal hepatic function. Empagliflozin
may be used in patients with hepatic impairment
Pharmacogenetics/genomics No data identified
Summary
Empagliflozin is the third SGLT2 inhibitor available in the US. Average change in A1C is generally < 1.0%.
Based on the clinical trial data, increasing the dose of empagliflozin from 10mg to 25mg does not appear to offer
additional meaningful efficacy. In the active comparator trial, the efficacy of empagliflozin was found to be similar
to glipizide and sitagliptin.
Advantages of empagliflozin include low risk of hypoglycemia and weight loss. Most recently, empagliflozin was
found to be the first diabetes drug to show a cardiovascular risk reduction. The study was conducted in patients with
a history of CV disease. Whether this finding is unique to empagliflozin or is a class effect of the SGLT2 inhibitors
is not known. Results for the cardiovascular outcomes trials for canagliflozin and dapagliflozin are expected in
2017 and 2019 respectively. It is unknown if the findings of the empagliflozin CV study applies to patients without
preexisting CV disease.
Adverse reactions most likely attributed to SGLT2 inhibitor mechanism of action include increased incidence of
genital mycotic infections, UTIs, osmotic diuresis and reduced intravascular volume related events.
References
Barnett AH, Mithal A, Manassie J, et al. EMPA-REG RENAL trial investigators. Efficacy and safety of
empagliflozin added toexisting antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a
randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014; 2(5):369-84.
Häring HU, Merker L, Seewaldt-Becker E, et al. EMPA-REG MET Trial Investigators. Empagliflozin as add-on to
metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes
Care. 2014 Jun;37(6):1650-9.
Häring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin plus sulfonylurea in patients
with type 2 diabetes. Diabetes Care 2013; 36: 3396-3404.
Haring HU, Merker L, Christiansen AV, et al. Empagliflozin for ≥76 weeks as add-on to metformin plus
sulfonylurea in patients with type 2 diabetes. American Diabetes Association 74th Scientific Sessions June 13-17,
2014 San Francisco, CA. [abstract 1077-P].
Ferrannini E, Berk A, Hantel S, et al. Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin.
An active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2
diabetes. Diabetes Care 2013; 36: 4015-4021.
October 2015 13
Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
Empagliflozin Monograph
Kovacs CS, Seshiah V, Swallow R, et al. Empagliflozin improves glycemic and weight control as add-on therapy to
pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-
controlled trial. Diabetes Obes Metab 2014; 16: 147-158.
Kovacs CS, Seshiah V, Merker L, et al. Empagliflozin (EMPA) for ≥76 weeks as add-on to pioglitazone with or
without metformin in patients with type 2 diabetes. American Diabetes Association 74th Scientific Sessions June
13-17, 2014 San Francisco, CA. [abstract 1055-P]
Merker L, Haring HU, Christiansen AV, et al. Empagliflozin for ≥76 weeks as add-on to metformin in patients with
type 2 diabetes. American Diabetes Association 74th Scientific Sessions June 13-17, 2014 San Francisco, CA.
[abstract 1074-P].
Ridderstale M, Andersen KR, Zeller C, et al. Comparison of empagliflozin and glimepiride as add-on to metformin
in patients with type 2 diabetes: a 104-week randomized, active-controlled, double-blind, phase 3 trial. Lancet
Diabetes Endocrinol 2014; 2: 691-700.
Roden M, Weng J, Eilbracht J, et al. EMPA-REG MONO trial investigators. Empagliflozin monotherapy with
sitagliptin as an active comparator in patients with type 2 diabetes: a randomised,double-blind, placebo-controlled,
phase 3 trial. Lancet Diabetes Endocrinol. 2013Nov;1(3):208-19.
Rosenstock J, Jelaska A, Frappin G, et al. Improved glucose control with weight loss, lower insulin doses, and no
increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese
inadequately controlled type 2 diabetes. Diabetes Care 2014; 37: 1815-1823.
Rosenstock J, Jelaska A, Wang F, et al. Empagliflozin as add-on to basal insulin for 78 weeks improves glycemic
control with weight loss in insulin–treated type 2 diabetes. American Diabetes Association 74th Scientific Sessions
June 13-17, 2014 San Francisco, CA. [abstract 1102-P].
Study 1245.33. A phase IIb, randomized, double-blind, placebo-controlled, parallel group, safety and efficacy study
of BI 10773 (10 mg and 25 mg) administered orally, once daily over 78 weeks in type 2 diabetic patients receiving
treatment with basal insulin (glargine, detemir, or NPH insulin only) with or without concomitant metformin and/or
sulfonylurea therapy and insufficient glycemic control
http://trials.boehringer-ingelheim.com/content/dam/internet/opu/clinicaltrial/com_EN/results/1245/1245.33_U12
3817-01-DS_DR.pdf
Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and
hypertension. Diabetes Care 2015; 38:420-8.
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
NEJM 2015; DOI: 10.1056/NEJMoa1504720
October 2015 14
Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
Empagliflozin Monograph
Abbreviations: BI=basal insulin; BL=baseline; CKD=chronic kidney disease; DBP=diastolic blood pressure; EMP=empagliflozin; FPG=fasting plasma glucose; GLM=glimepiride; MDI=multiple dose insulin;
MET=metformin; na=not applicable; NS=not shown; PBO=placebo; PIO=pioglitazone; SBP=systolic blood pressure; SIT=sitagliptin; SU=sulfonylurea
October 2015 15
Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov
Empagliflozin Monograph
¶Values for CKD study shown according to eGFR subgroups (eGFR ≥60 to <90/eGFR ≥30 to <60)- Empagliflozin was not effective in the subgroup with eGFR ≥15 to <30 (values not shown in table)
§Incidence of UTIs (male/female) for those with eGFR ≥60 to <90: 8.3/23.7 (EMP10), 3.3/19.4 (EMP25), 8.9/25.6 (PBO). UTIs for those with eGFR ≥30 to <60. 5.6/31.3 (EMP25), 3.8/30.9 (PBO)
^Incidence of genital infections (male/female) for those with eGFR ≥60 to <90. 10/2.6(EMP10), 0/13.9 (EMP25), 3.6/10.3 (PBO). Genital infections for those with eGFR ≥30 to <60. 1/9/3/8 (EMP25), 0/9/1/2
(PBO)
October 2015 16
Updated version may be found at www.pbm.va.gov or vaww.pbm.va.gov